TY - JOUR
T1 - A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific Inflammatory Mediators and Pathways in Crohn’s Disease
AU - Elfiky, Ahmed M. I.
AU - Hageman, Ishtu L.
AU - Becker, Marte A. J.
AU - Verhoeff, Jan
AU - Li Yim, Andrew Y. F.
AU - Joustra, Vincent W.
AU - Mulders, Lieven
AU - Fung, Ivan
AU - Rioja, Inmaculada
AU - Prinjha, Rab K.
AU - Smithers, Nicholas N.
AU - Furze, Rebecca C.
AU - Mander, Palwinder K.
AU - Bell, Matthew J.
AU - Buskens, Christianne J.
AU - D’Haens, Geert R.
AU - Wildenberg, Manon E.
AU - de Jonge, Wouter J.
N1 - Funding Information: This work was supported by the European Union’s Horizon 2020 research and innovation program under grant agreement no. ITN-2014-EID-641665. WJ was funded by a grant from the Dutch Economic Affairs Top Sector Life Sciences and Health (LSH)—Top Consortia for Knowledge and Innovation’s (TKI), grant no. TKI-LSH T2017, and the European Crohn’s and Colitis Organization (ECCO) Pioneer Grant, 2018. Furthermore, this project was in collaboration with GlaxoSmithKline Research Collaboration Agreement No. COL300035595. Publisher Copyright: © 2022 by the authors.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Background: Myeloid cells are critical determinants of the sustained inflammation in Crohn’s Disease (CD). Targeting such cells may be an effective therapeutic approach for refractory CD patients. Bromodomain and extra-terminal domain protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also possess wide-ranging toxicities. In the current study, we make use of a BET inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid cells. Methods: We profiled CES1 protein expression in the intestinal biopsies, peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were evaluated in healthy donor CD14+ monocytes and fCD cells, using cytometric beads assay or RNA-sequencing. Results: CES1 was specifically expressed in monocyte, macrophage, and dendritic cell populations in the intestinal tissue, peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1β, IL6, and TNFα secretion from healthy donor CD14+ monocytes and fCD immune cells, with 10- to 26-fold more potency over iBET in isolated CD14+ monocytes. Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior potency over iBET. Conclusions: We demonstrate specific CES1 expression in mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells and exerts robust anti-inflammatory effects, which could be beneficial in refractory CD patients.
AB - Background: Myeloid cells are critical determinants of the sustained inflammation in Crohn’s Disease (CD). Targeting such cells may be an effective therapeutic approach for refractory CD patients. Bromodomain and extra-terminal domain protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also possess wide-ranging toxicities. In the current study, we make use of a BET inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid cells. Methods: We profiled CES1 protein expression in the intestinal biopsies, peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were evaluated in healthy donor CD14+ monocytes and fCD cells, using cytometric beads assay or RNA-sequencing. Results: CES1 was specifically expressed in monocyte, macrophage, and dendritic cell populations in the intestinal tissue, peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1β, IL6, and TNFα secretion from healthy donor CD14+ monocytes and fCD immune cells, with 10- to 26-fold more potency over iBET in isolated CD14+ monocytes. Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior potency over iBET. Conclusions: We demonstrate specific CES1 expression in mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells and exerts robust anti-inflammatory effects, which could be beneficial in refractory CD patients.
KW - BET inhibitor
KW - CES1
KW - IBD
UR - http://www.scopus.com/inward/record.url?scp=85138421433&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells11182846
DO - https://doi.org/10.3390/cells11182846
M3 - Article
C2 - 36139421
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 18
M1 - 2846
ER -